Warfarin sensitivity is associated with increased hospital mortality in critically Ill patients

Background: Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Warfarin sensitivity has been reported to be associated with increased incidence of international normalized ratio (INR) > 5. However, whether warfarin sensitivity is a risk factor for adverse outcomes in critically ill patients remains unknown. In the present study, we aimed to evaluate the utility of different machine learning algorithms for the prediction of warfarin sensitivity and to determine the impact of warfarin sensitivity on outcomes in critically ill patients. Methods: Nine different machine learning algorithms for the prediction of warfarin sensitivity were tested in the International Warfarin Pharmacogenetic Consortium cohort and Easton cohort. Furthermore, a total of 7,647 critically ill patients was analyzed for warfarin sensitivity on in-hospital mortality by multivariable regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. Results: We found that logistic regression (AUC = 0.879, 95% CI: 0.834–0.924) was indistinguishable from support vector machine with a linear kernel, neural network, AdaBoost and light gradient boosting trees, and significantly outperformed all the other machine learning algorithms. Furthermore, we found that warfarin sensitivity predicted by the logistic regression model was significantly associated with worse in-hospital mortality in critically ill patients with an odds ratio (OR) of 1.33 (95% CI, 1.01–1.77). Conclusions: Our data suggest that the logistic regression model is the best model for the prediction of warfarin sensitivity clinically and that warfarin sensitivity is likely to be a risk factor for adverse outcomes in critically ill patients.